Dysfonction chronique post transplantation pulmonaire, enseignements en 2018 de COLT et SysCLAD
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Dysfonction chronique post transplantation
pulmonaire, enseignements en 2018 de COLT et
SysCLAD
CMJ, Grenoble le 05-04-2018
Pr. Christophe Pison, au nom des
consortia SysCLAD et COLT
Service Hospitalier Universitaire
Pneumologie Physiologie
Pôle Thorax et Vaisseaux
CHU de Grenoble
Inserm1055, Laboratoire de
Bioénergétique Fondamentale et
Appliquée
Biologie Environnementale et
Systémique – BEeSYRelations d’intérêts Aides et Objets Travels, Meeting, Speakers fees to Pr. Ch. Pison Clinical Research to my Hospital COPD-Nutrition, Asthma, Pulmonary Hypertension, Lung Transplantation Pharmas et contrat avec CHU des Alpes Actélion Astra Zeneca Bayer Boehringer Ingelheim Gilead GlaxoSmithKline Lilly Novartis Nutricia-Danone Seb Pfizer Stallergenes Dispositifs & Soins à domicile Therakos, PneumRx, Medwin, PumonX, Holaira AGIR@dom, Vitlalaire, Orkyn, Vitalaire, SOS Oxygène 2
Groupe de Transplantation Pulmonaire
1990-2016 > 260 greffes
• Anesthésistes - Réanimateurs
P Albaladejo, C Allègre, D Anglade, D Bedague, O Carle, M Casez-Brasseur, D Colas, G
Dessertaine, Y Dubois, M Durand, G Francony, MR Marino, D Protar, S Robin, M Rossi-
Blancher
• Chirurgiens Cardiaques, Thoraciques & Vasculaires
D Angelescu, PY Brichon, O Chavanon, G Frey, R Hacini, A Pirvu, P Porcu
• Pneumologues, Cardiologues, Infectiologues, Psychiatre
A Boignard, H Bouvaist, A Briault, B Camara, J Claustre, M Dubuc, S Quétant, P Pavèse,
C Pison, C St-Raymond
• Pharmaciens Cliniciens et Recherche clinique
P Bedouch, S Chanoine, C Chérion
• Imagerie et Pathologie
G Ferretti, A Jankowski, E Reymond, O Stephanov,
• Coordination, Cadres, Système d’information, Psychologues, Assurance Qualité
C Fleurence, C Segond, E Tourral, M. Guyot, L Altoukhovitch, F Imburchia
• Soins de suite, Réhabilitation et Soins à domicile
Centre Henri Bazire & AGIR@dom
3360, 241 (file active) patients, 2006-2017
Pédiatres : S. Douchin, G. Blaysat
Cardiologie, Réhabilitation : H. Bouvaist, S. Marlière, M. Noirclerc,
M. Salvat, C. Saunier, E. Vautrin
Imageurs : G. Ferretti, A. Jankowski, F. Thony, E. Reymond
Pneumologues, Interniste : B. Camara, J. Claustre, S. Quêtant, C. Saint-
Raymond, C. Pison, B. Imbert
Fonctionnalistes : B. Aguilaniu, B. Wuyam, S. Doutreleau
Pharmaciens cliniciens, recherche clinique
P. Bedouch, S. Chanoine, M. Jondot, B. Rey-Robert
Soins à domicile : Agir à Dom
4CRCM Adulte et Pédiatrique du CHUGA
Corps médical Corps médical
• B Camara (responsable médical) • I Pin (responsable médical)
• S Quetant • C LLéréna
IDE Coordinatrice IDE Coordinatrice
• C Segond • C Turblin, M Cheik
Masseur kinésithérapeute Masseur kinésithérapeute
• JC Benitez • V Vion
Diététicienne Diététicienne
• C Neveu • Lise Joly
Psychologue Psychologue
• L Altoukovich • A Simon Léger
Assistante sociale Assistante sociale
• Magali Fabre • D Cucchi
Secrétariat Secrétariat
• E Julien Binard • F. Allamanno
5Historique de la transplantation pulmonaire 1905, 1ère greffe cœur chiot anastomosé au cou d’un chien, Alexis Carrel, Lyon 1949, 1ère greffe d’un poumon chez le chien, Pr. Henri Métras, Marseille 1952, 1ère greffe rénale donneur vivant, Jean Hamburger 1963, 1ère greffe pulmonaire, Pr. J. Hardy, Missippi 1981, 1ères greffes cardio-pulmonaires Pr. N. Shumway, San Francisco 1982, 1ère greffe cardio-pulmonaire en Europe, Pr. C. Cabrol, Paris 1983, mise à disposition Cyclosporine A, laboratoire Sandoz, Novartis 1983, 1ère greffes mono-pulmonaire viables, Pr. J. Cooper, Toronto 1983, 1ère greffe pulmonaire pour mucoviscidose, Pr. M.H. Yacoub, UK 1986, 1ère greffes double pulmonaire en bloc, Pr. J. Cooper, Toronto 1989, 1ère greffe double mono-pulmonaire séquentielle sans CEC, Pr. A. Bisson, Foch 2011, 1ère série 11 EVLP, Pr. Shaf Keshjavjee, Toronto 11 centre de greffes pulmonaires, dont 8 pour la mucoviscidose en France ABM, 1993 à VI-2014, 3 701Tx pulmonaires, 30% soit 1106 pour mucoviscidose ISHLT 1995 àVI-2014, 45 683 Tx pulmonaires, 16,2% soit 7419 pour mucoviscidose6
SysCLAD consortium, COLT & STCS Cohort of lung Transplantation-COLT associating surgeons, anaesthetists - intensivists, physicians, research assistants; Bordeaux: J. Jougon, J-F. Velly, H. Rozé, E. Blanchard, C. Dromer; Bruxelles: M. Antoine, M. Cappello, M. Ruiz, Y. Sokolow, F. Vanden Eynden, G. Van Nooten, L. Barvais, J. Berré, S. Brimioulle, D. De Backer, J. Créteur, E. Engelman, I. Huybrechts, B. Ickx, T. J. C. Preiser, T. Tuna, L. Van Obberghe, N. Vancutsem, J-L. Vincent, P. De Vuyst, I. Etienne, F. Féry, F. Jacobs, C. Knoop, J. L. Vachiéry, P. Van den Borne, I. Wellemans, G. Amand, L. Collignon, M. Giroux; Grenoble: D. Angelescu, P.-Y. Brichon, O. Chavanon, G. Frey, R. Hacini, C. Martin, A. Pirvu, P. Porcu; P. Albaladejo, C. Allègre, A. Bataillard, D. Bedague, E. Briot, M. Casez-Brasseur, D. Colas, G. Dessertaine, M. Durand, G. Francony, A. Hebrard, M. R. Marino, B. Oummahan, D. Protar, D. Rehm, S. Robin, M. Rossi-Blancher, C. Augier, P. Bedouch, A. Boignard, H. Bouvaist, A. Briault, B. Camara, J. Claustre, S. Chanoine, M. Dubuc, S. Quétant, J. Maurizi, P. Pavèse, C. Pison, C. Saint-Raymond, N. Wion, C. Chérion; Lyon: R. Grima, O. Jegaden, J-M. Maury, F. Tronc, C. Flamens, S. Paulus, J-F. Mornex, F. Philit, A. Senechal, -C. Glérant, S. Turquier, D. Gamondes, L. Chalabresse, F. Thivolet-Bejui, C Barnel, C. Dubois, A. Tiberghien; Paris, Hôpital Européen Georges Pompidou: F. Le Pimpec-Barthes, A. Bel, P. Mordant, P. Achouh, V. Boussaud, R. Guillemain, D. Méléard, M. O. Bricourt, B. Cholley, V. Pezella; Marseille: G. Brioude, X. B. D’Journo, C. Doddoli, P. Thomas, D. Trousse, S. Dizier, M. Leone, L. Papazian, F. Bregeon, A. Basire, B. Coltey, N. Dufeu, H. Dutau, S. Garcia, J. Y. Gaubert, C. Gomez, S. Laroumagne, A. Nieves, L. C. Picard, M. Reynaud- Gaubert, V. Secq, G. Mouton; Nantes: O. Baron, C. Brossaud, E. Durand, M. Durand, P. Lacoste, C. Perigaud, J. C. Roussel, I. Danner, A Haloun A. Magnan, A Tissot, T. Lepoivre, M. Treilhaud, K. Botturi-Cavaillès, S. Brouard, R. Danger, J. Loy, M. Morisset, M. Pain, S. Pares, D. Reboulleau, P.-J. Royer; Le Plessis Robinson, Hôpital Marie Lannelongue: D. Fabre, E. Fadel, O. Mercier, S. Mussot, F. Stephan, P. Viard, J. Cerrina, P. Dorfmuller, S. Feuillet, M. Ghigna, Ph. Hervé ; F. Le Roy Ladurie, V. Thomas de Montpreville, L. Lamrani; Paris, Hôpital Bichat: Y. Castier, P. Mordant, P. Cerceau, P. Augustin, S. Jean-Baptiste, S. Boudinet, P. Montravers, O. Brugière, G. Dauriat, G. Jébrak, H. Mal, A. Marceau, A-C. Métivier, G. Thabut, E. Lhuillier, C. Dupin, V. Bunel; Strasbourg: P. Falcoz, G. Massard, N. Santelmo, G. Ajob, O. Collange O. Helms, J. Hentz, A. Roche, B. Bakouboula, T. Degot, A. Dory, S. Hirschi, S. Ohlmann-Caillard, L. Kessler, R. Kessler, A. Schuller, B. Renaud-Picard, K. Bennedif, S. Vargas; Suresnes: P. Bonnette, A. Chapelier, P. Puyo, E. Sage, J. Bresson, V. Caille, C. Cerf, J. Devaquet, V. Dumans-Nizard, M. L. Felten, M. Fischler, A. G. Si Larbi, M. Leguen, L. Ley, N. Liu, G. Trebbia, S. De Miranda, B. Douvry, F. Gonin, D. Grenet, A. M. Hamid, H. Neveu, F. Parquin, C. Picard, A. Roux, M. Stern, F. Bouillioud, P. Cahen, M. Colombat, C. Dautricourt, M. Delahousse, B. D’Urso, J. Gravisse, A. Guth, S. Hillaire, P. Honderlick, M. Lequintrec, E. Longchampt, F. Mellot, A. Scherrer, L. Temagoult, L. Tricot, M. Vasse, C. Veyrie, L. Zemoura; Toulouse: J. Berjaud, L. Brouchet, M. Dahan, F. O. Mathe, H. Benahoua, M. DaCosta, I. Serres, V. Merlet-Dupuy, M. Grigoli, A. Didier, M. Murris, L. Crognier, O. Fourcade. Swiss lung Transplant centers Lausanne-Geneva: T. Krueger, H. B. Ris, M. Gonzalez, J.-D. Aubert, L. P. Nicod, B. J. Marsland, C. Berutto, T. Rochat, P. Soccal, Ph. Jolliet, A. Koutsokera, C. Marcucci, O. Manuel, E. Bernasconi, M. Chollet, F. Gronchi, C. Courbon; Zurich: S. Hillinger, I. Inci, P. Kestenholz, W. Weder; R. Schuepbach, M. Zalunardo, C. Benden, U. Buergi, L. C. Huber, B. Isenring, M. M. Schuurmans, A. Gaspert, D. Holzmann, N. Müller, T. Rechsteiner, C. Schmid, B. Vrugt. We would like to thank the following collaborators of the Swiss Lung Transplantation Centers for their contribution in data collection and/or project coordination (alphabetical order): E. Catana, C. Cowaloosur-Noirat, M. F. Derkenne, JL Dreifuss, P. Grendelmeier, J. Hartwig, N. Lourenco, M. Magno, H. Muller- McKenna, E. Perret, and K. Zangger. Swiss Transplant Cohort Study-STCS: Rita Achermann, Patrizia Amico, John-David Aubert, Philippe Baumann, Guido Beldi, Christian Benden, Christoph Berger, Isabelle Binet, Pierre-Yves Bochud, Elsa Boely, Heiner Bucher, Leo Bühler, Thierry Carell, Emmanuelle Catana, Yves Chalandon, Sabina de Geest, Olivier de Rougemont, Michael Dickenmann, Michel Duchosal, Laure Elkrief, Thomas Fehr, Sylvie Ferrari- Lacraz, Christian Garzoni, Paola Gasche Soccal, Christophe Gaudet, Emiliano Giostra, Déla Golshayan, Karine Hadaya, Jörg Halter, Dominik Heim, Christoph Hess, Sven Hillinger, Hans H. Hirsch, Günther Hofbauer, Uyen Huynh-Do, Franz Immer, Richard Klaghofer, Michael Koller (Head of the data center), Bettina Laesser, Roger Lehmann, Christian Lovis, Oriol Manuel, Hans-Peter Marti, Pierre Yves Martin, Luca Martinolli, Pascal Meylan, (Head, Biological samples management group), Paul Mohacsi, Philippe Morel, Ulrike Mueller, Nicolas J. Mueller (Chairman Scientific Committee), Helen Mueller-McKenna (Head of local data management), Antonia Müller, Thomas Müller, Beat Müllhaupt, David Nadal, Manuel Pascual (Executive office), Jakob Passweg, Juliane Rick, Eddy Roosnek, Anne Rosselet, Silvia Rothlin, Frank Ruschitzka, Urs Schanz, Stefan Schaub, Aurelia Schnyder, Christian Seiler, Susanne Stampf, Jürg Steiger (Head, Executive Office), Guido Stirnimann, Christian Toso, Christian Van Delden (Executive office), Jean-Pierre Venetz, Jean Villard, Madeleine Wick (STCS coordinator), Markus Wilhelm, and Patrick Yerly. SME and Platforms Biomax (Munich, Germany): A. Fritz, D. Maier; Finovatis (Lyon, France): K. Desplanche, D. Koubi; GATC (Germany): F. Ernst, T. Paprotka, M. Schmitt, B. Wahl; Novasdicovery (Lyon, France): J.-P. Boissel, G. Olivera-Botello; Prométhée Proteomics Platform (Grenoble, France): C. Trocmé, B. Toussaint, S. Bourgoin-Voillard, M. Séve; Inserm U823, Université GrenobleAlpes (Grenoble, France): M. Benmerad, V. Siroux, R. Slama; European Institute for Systems Biology & Medicine (Lyon, France): C. Auffray, B. de Mulder, Mazein, J. Pellet 7
Achilles‘ heels in Lung Transplantation
Shortage of grafts, Primary Graft Dysfunction
Chronic Lung Allograft Dysfunction - CLAD
-15%, 3 months BOS in 50% at 5 years
different patterns
- 4% / year
30% cause of death > 1 year
median survival 1.5 years, if early onset
8Adult Lung Transplants
Number of Transplants by Year and Procedure Type
4500
4041 39904122
4000 Bilateral/Double Lung 3759 3752
Number of Transplants
3462
3500 Single Lung 3182
3000 28412907
2706
2483
2500
2138
19031938
2000 1713
1635
1417 1494
1500 1305 1445
11601296
1055
1000 874
664
500 385
160
5 6 32 69
0
NOTE: This figure includes only the adult lung
transplants that are reported to the ISHLT Transplant
Registry. As such, this should not be construed as
2017 representing changes in the number of adult lung
transplants performed worldwide.
JHLT. 2017 Oct; 36(10): 1037-1079Adult Lung Transplants
Major Indications by Year (%)
100 COPD A1ATD CF IIP ILD-not IIP Retransplant
80
% of Transplants
60
40
20
0
Transplant Year
2017
JHLT. 2017 Oct; 36(10): 1037-1079Adult Lung Transplants
Kaplan-Meier Survival by Era
(Transplants: January 1990 – June 2015)
100
Median survival (years):
1990-1998: 4.2; Conditional=7.1;
1999-2008: 6.1; Conditional=8.5;
75 2009-6/2015: NA; Conditional=NA
1990-1998 vs. 1999-2008: pSystems Medicine
Systems prediction of Chronic Lung Allograft Dysfunction
SysCLAD
Snyderman et al. Biotechnol. J. 2012;7:973-9 12PHRC 2009
13Roedder et al. Genome Medicine 2011;3:37 14
Risk factors Immune system Graft CLAD
Bronchiolitis Obliterans
Innate immunity
Syndrome
IR Airway epithelium
Environnement Injuries
TLR, RAGE
DAD DAMPS/Alarmins EMT
Neutrophils IL-8
GERD HMGB1, S100, HSP Growth Factors
IL-6 CCL2
CCL5 TGF-β, VEGF, PDGF
PGD Eosinophils
Infections Macrophages M1/M2
Proteases Small airway obstruction
PAMPS
Pollutants LPS, viral RNA TLR NK
Dendritic cell editing
Graft destruction
Wound
Chemotaxis ROS
Antigen presentation
Specific factors: early onset DAD
Adaptive immunity Restrictive Allograft
Self-Ag exposure Allogenicity
MMP Healing Syndrome
DSA
MHC Destruction of
Treg terminal
mismatch Th1/Th17
bronchioles, alveolar
Inflammation obliteration
TNFα, IL1β
IL-17
Tissu destruction Small airway
Autoimmunity Perforin/Granzyme
obstruction
α-colV, α-kα1Tub Specific factors: late onset DAD,
Self Ag presentation
alarmins (S100, HMGB1),
immunosuppression, eosinophilia
Royer et al. Transplantation 2016; 100: 1083-14 Immunosuppression 15Design, Methods, Objectives COLT French cohort since 09-2009, 11 centres + Bruxelles Swiss Transplant Cohort Study, STCS since 2008 in Lausanne- Genève, Zurich I-2018, 1506 transplanted 802 reached year-3, or displayed CLAD before year-3, or died before year-3 Donors: day 0 clinics HLA lung tissue Recipients: before Tx, day-0 Tx, M6-M12 post LTx Clinics - e.CRF Pollution by geolocalization Blood: HLA, transcriptomics x 2, proteomics x 2, miRNA x 1, lymphocytes subpopulations, exome sequencing BAL: microbiote & macrophages polarization, proteomics x 2 Objective: to predict CLAD @ year-3, as soon as year-1 16
COLT
Research of early predictive factors of CLAD
Towards 4P medicine ?
Inclusion Transplantation
Chronic
rejection
V0 V1 V2 V3 5 years
samplesCOLT
C Knoop
S Mussot
M Stern
O Brugière (Bichat),
V Boussaud (HEGP)
R Kessler
A Magnan
A Tissot
C Benden
L Nicod
JD Aubert
JF Mornex
C Dromer
C Pison
M Dahan
M Reynaud-GaubertPatients STCS 2008-2014
60
50
40
30 Inclus
stables (2016)
20
10
0
dont 2008 2009 2010 2011 2012 2013 2014COLT / SysCLAD Story
INSERM
2008: R Pays de Loire
LT program
ABM
VLM / AGL Novartis, Sanofi, 1200°
Astellas
2009: 500° 07 2017:
PHRC National Inclusions: 1804
Transplanted: 1451
Recherche Biomédicale Recherche Non InterventionnelleAvancement de la cohorte / centre
Cohort progression • 654 patients with 3 years of follow-up post transplant • 270 patients with 5 years of follow-up • 477 patients deceased including 273
Current Classification of
Chronic Lung Allograft Dysfunction
CLAD
Confounding factors
BOS RAS
12 adjudication meetings with 7 experts
23Dysfonction Chronique du Greffon Classification of adjudicated patients after 3 years post transplant
Biocollection • Number of samples: 150 000 • > 90 % in Nantes « CRB » (certified since 24th July 2014, NF S96-900 de l’Afnor
Dysfonction Chronique du Greffon
Classification of adjudicated patients after 3 years post transplant
• Nov 2017: 1st adjudications at 5 years: 250 patients « stable » at 3 yearsFingers & Hand prints to predict CLAD
1. Clinicome 1st year
2. Pollution by geolocalization
3. Recipient exome genome sequencing
4. BAL / Plasma proteome
5. Immuno-monitoring, PBMC, HLA, DSA
6. Transcriptome and miRNA
7. Lung microbiote and macrophage polarization
27Complex biomarkers: transcriptome in patients
waiting for lung transplant
samples
Hierarchical cluster Helthy volunteers (HV)
Cystic fibrosis
Pulmonary Hypertension
Signature of respiratory failure
Gènes
Over expressed genes
Under expressed genes Signature PAH
Signature Cystic Fibrosis
J Chesné, Plos One 2014Clinicome, outcomes at year-3
Stable
Bronchiolitis Obliterans Syndrome - BOS
RAS
Koutsokera et al. 2016, in revision 29Clinicome, prediction at 3 years
3031
Clinicome, prediction at 3 years
32Clinicome, prediction at 3 years
33Clinicome, prediction at 3 years
34Clinicome, prediction at 3 years
35Chronic Effects of Air Pollution Benmerad et al. ERJ 2017; 49: 1-12 36
Chronic Effects of Air Pollution Benmerad et al. ERJ 2017; 49: 1-12 37
Chronic Effects of Air Pollution
Model 1
Model 0
Model 2
Benmerad et al. ERJ 2017; 49: 1-12 3839
Chronic Effects of Air Pollution Benmerad et al. ERJ 2017; 49: 1-12 40
MMP9 Story
Airway epithelial cells exposed to allogeneic T cells produce MMP9 through a CCL2/CCR2
pathway: implications for chronic lung allograft dysfunction.
epithelial cells (BEC)
Donor’s Bronchial
Immune cells
Recipient’s
Modification of BEC profile
Pain M, Royer PJ, AJT 2016Airway epithelial cells exposed to allogeneic T cells
produce MMP9 through a CCL2/CCR2 pathway:
implications for chronic lung allograft dysfunction
A B C
1200 * 10000 100
BOS
Stable
80
900
RAS
Sensitivity %
1000
MMP9 (pg/mL)
60
ng/ml
600
Area:0.8561
40
100
pRegulatory T lymphocytes profile as a possible
predictive biomarker of the Bronchiolitis
Obliterans Syndrome after lung transplantation
Maxim Durand1,2,3*, Philippe Lacoste2,3*, Carole Brosseau1,2,
Eugénie Durand2, Jennifer Loy2, Pierre Joseph Royer2, Antoine Magnan2,
Sophie Brouard1 & COLT Consortium
1 Center for Research in Transplantation and Immunology, INSERM U1064, Nantes, France
2 l’institut du thorax, INSERM U1087/CNRS U6291, Nantes, France
3 Université de Nantes, Nantes, FranceConclusion
• Increase of Tregs proportion with a memory phenotype early after TP for patients who will declare
a BOS in the five years.
100 100
90
BOS free survival (%)
80 80
70
Sensitivity%
60 60 **
50
40 40
30
20 20 Tregs among CD4 < 2,08 %
10 Log rank p = 0,0035 Tregs among CD4 > 2,08 %
0 0
0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60
100% - Specificity% Monts post TP
• New potential biomarker of the BOS occurrence, which could help to manage CLAD after lung
transplantation in the next decades.Blood Gene Expression Predicts
Bronchiolitis Obliterans Syndrome Appearance
After Lung Transplantation
Richard Danger*, Pierre-Joseph Royer*,
Damien Reboulleau, Eugénie Durand, Jennifer Loy, Adrien Tissot, Philippe Lacoste, Antoine Roux, Martine
Reynaud-Gaubert, Carine Gomez, Romain Kessler, Sacha Mussot, Claire Dromer, Olivier Brugière, Jean-
François Mornex, Romain Guillemain, Marcel Dahan, Christiane Knoop, Karine Botturi, Christophe Pison,
Angela Koutsokera, Laurent P. Nicod,
Sophie Brouard*, Antoine Magnan*
and the COLT and SysCLAD ConsortiaPrediction of BOS: independent validation
• Validation of genes associated with BOS appearance
-individual qPCR
-samples from new patients:
n= 13 STA & 11 PRED
independent validation
ROC curves: AUC= 0.83 AUC= 0.77 AUC= 0.78 Excellent discriminative ability
• Prediction of BOS appearance
3 genes to predict BOS
POU2AF1: POU class 2 associating factor 1
BLK: B lymphoid tyrosine kinase
TCL1A: T-cell leukaemia/lymphoma 1ABlood Gene Expression Predicts Bronchiolitis
Obliterans Syndrome Appearance
After Lung Transplantation
• Identification of 3 genes as predictive biomarkers of BOS
• Whole blood and qPCR: non-invasive and compatible with clinical settings
• Suggests a role of B cells in BOS mechanisms
patent: EP16306125.2
work submitted
Validation of these 3 genes in a large prospective cohortProteomics Claustre et al. In preparation 48
Lung Microbiote & BAL Macrophage polarization
BAL cells Lung microbiota
(CHUV standards) (Data from Hilty M et al. PLoS ONE 2010)
Macrophages > 85% Bacteroidetes 42.0%
Neutrophils < 3% Firmicutes 32.5%
Eosinophils < 0.5% Proteobacteria 12.3%
Lymphocytes < 12% Fusobacteria 10.2%
Bronchial cells < 10% Actinobacteria 2.6%
RNA isolation DNA isolation
Real-time PCR-based quantification Real-time PCR-based quantification
Balanced microbiota Dysbiosis
Bernasconi et al. AJRCCM 2016; 194: 1252-63 4951
Proteomics Claustre et al. 2016, submitted 52
samples
clinical information
gene expression (mRNA)
toward s a personal handprint
Integration in SysCLAD
DNA mutations, copy-number,
and structural variations
Feature matrix
microRNA expression
Proteomics
Microbiome
Exposome
53Identification of early biomarkers of CLAD
Blood (Paxgene)
BAL Geolocalisation
DNA Clinical data
Plasma/BAL PBMC
54Integration in SysCLAD
towards a personal handprint or limits of single biomarker
Nature 469, 156–157 (13 January 2011)
Only one to monitor acute rejection after cardiac transplantation -AlloMap® 55Side effects
C Knoop
• Positive chemistry
M Stern S Mussot
O Brugière (Bichat),
V Boussaud (HEGP)
• Network of surgeons, pulmonologists, R Kessler
A Magnan
researchers. A Haloun
C Benden
L Nicod
JD Aubert
JF Mornex
• New labs driven to Lung Tx C Dromer
C Pison
(S Brouard, V Siroux…)
M Dahan
M Reynaud-Gaubert
• Gift to youngersCOLT demain • Optimization: • Simplified CRF • Data clinic • Validation of biomarkers • Complex signatures (handprints), score prédictif du CLAD • Biomarkers at 5 years of follow-up • Pre-transplant biomarkers • COLT opened for other teams / Laboratories (valorization of the biocoll) • Personalized medicine in LT through system approach
Agusti A et al. AJRCCM 2015 58
Remerciements PHRC 2009
1. Durand M, Lacoste P, Danger R, Jacquemont L, Brosseau C, Durand E, Tilly G, Loy J, Foureau A, Royer PJ, Tissot A, Roux A, Reynaud-Gaubert M, Kessler R,
Mussot S, Dromer C, Brugière O, Mornex JF, Guillemain R, Claustre J, Degauque N, Magnan A, Brouard S; COLT and SysCLAD Consortia. High circulating
CD4(+)CD25(hi)FOXP3(+) T-cell sub-population early after lung transplantation is associated with development of bronchiolitis obliterans syndrome. J Heart
LungTransplant. 2018 Mar 20
2. Danger R, Royer PJ, Reboulleau D, Durand E, Loy J, Tissot A, Lacoste P, Roux A, Reynaud-Gaubert M, Gomez C, Kessler R, Mussot S, Dromer C, Brugière O,
Mornex JF, Guillemain R, Dahan M, Knoop C, Botturi K, Foureau A, Pison C, Koutsokera A, Nicod LP, Brouard S, Magnan A; COLT and SysCLAD Consortia. Blood
Gene Expression Predicts Bronchiolitis Obliterans Syndrome. Front Immunol. 2018 Jan 11;8:1841.
3. Royer PJ, Henrio K, Pain M, Loy J, Roux A, Tissot A, Lacoste P, Pison C, Brouard S, Magnan A; COLT consortium. TLR3 promotes MMP-9 production in primary
human airway epithelial cells through Wnt/β-catenin signaling. Respir Res. 2017 Dec 13;18(1):208
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